Identification of 4-[1-[3-chloro-4-[N'-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid as a potent, orally active VLA-4 antagonist.
Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.
Muro
Fumihito
F
Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. muro.fumihito.iy@daiichisankyo.co.jp
Iimura
Shin
S
Yoneda
Yoshiyuki
Y
Chiba
Jun
J
Watanabe
Toshiyuki
T
Setoguchi
Masaki
M
Iigou
Yutaka
Y
Takayama
Gensuke
G
Yokoyama
Mika
M
Takashi
Tohru
T
Nakayama
Atsushi
A
Machinaga
Nobuo
N
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy; D001565:Benzoates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D010539:Permeability; D011758:Pyrroles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats
C534076:4-(1-(3-chloro-4-(N'-(5-fluoro-2-methylphenyl)ureido)phenylacetyl)-(4S)-fluoro-(2S)-pyrrolidinylmethoxy)benzoic acid; D000893:Anti-Inflammatory Agents; D001565:Benzoates; D039041:Integrin alpha4beta1; D011758:Pyrroles